Functional diagnostics and ex-vivo screening of erlotinib and nintedanib in non-small cell lung carcinoma: Implications for multidrug resistance and personalized therapy
2023
Аутори:
Dinić, JelenaPodolski-Renić, Ana
Dragoj, Miodrag
Jovanović Stojanov, Sofija
Stepanović, Ana
Lupšić, Ema
Pajović, Milica
Petrović Rodić, Dušica
Marić, Dragana
Ercegovac, Maja
Pešić, Milica
Тип документа:
Конференцијски прилог (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт:
Background: Multidrug resistance (MDR) hampers tyrosine kinase inhibitor (TKI) efficacy in non-small cell lung carcinoma (NSCLC). ABC transporters ABCB1, ABCC1, and ABCG2 trigger MDR by effluxing drugs from cancer cells. We studied erlotinib and nintedanib effects in patient-derived NSCLC cultures, MDR phenotype impact, and genetic alterations influencing drug response.
Methods: ABC transporter expression in 10 NSCLC patient-derived cell cultures was assessed after TKI treatment via immunofluorescence assay which enables discrimination between cancer and stromal cells. Erlotinib (1 µM – 4 µM) and nintedanib (2.5 µM – 20 µM) were used in clinically relevant concentrations. Whole exome sequencing was employed to analyze genetic alterations in NSCLC samples.
Results: Erlotinib selectively inhibited cancer cell growth (IC50: 0.25 µM – 3.2 µM). It increased ABCC1 expression in 4/10 cultures and ABCB1/ABCG2 in 2/10 cultures. Erlotinib induced MDR markers expression at all concentrations. Nintedanib stimulated cancer cell growth at lower concentrations (˂10 µM) and caused 90% cell death at higher concentrations (˃15 µM), enriching the culture with cancer cells with high expression of ABCB1, ABCC1, and ABCG2. TKIs had no impact on MDR marker expression in stromal cells. Genetic alterations without clinical relevance for NSCLC were found in EGFR, ALK, ROS1, RET, and BRAF. L858R mutation in EGFR, indicated for erlotinib treatment, was detected in one patient, although all patients were responsive to erlotinib. Genetic alterations related to drug response were found in ABCB1 (7/10 patients) and ABCG2 (1/10 patients).
Conclusions: The employed functional diagnostics approach can effectively assess how erlotinib and nintedanib influence the MDR phenotype for individual patients. The ex-vivo screening system utilized in this study identifies the sensitivity of cancer and stromal cells and the correlation between response and their MDR profile, as well as the dependence of drug response on genetic alterations. This approach holds great promise for advancing personalized treatment strategies in NSCLC.
Финансирање / пројекти:
- TargetedResponse - Functional diagnostics in non-small cell lung carcinoma: A new concept for the improvement of personalized therapy in Serbian patients (RS-ScienceFundRS-Ideje-7739737)
У:
- Abstract book: Molecular Analysis for Precision Oncology Congress 2023; 2023 Oct 4-6; Paris, France. Elsevier; 2023. p. 12. (ESMO Open; Vol. 8; Suppl. 1S5).